Cancer is a leading cause of death in the industrialized world and despite years of research many types of cancer lack an effective therapeutic treatment. This is especially true for cancers that are characterized by the presence of large, solid tumors since it is difficult to deliver an effective dose of a chemotherapeutic agent to the interior of a large tumor mass with a degree of selectivity. Moreover, due to the genetic instability of tumor cells, a tumor tissue can rapidly acquire resistance to standard therapeutic regimens.
In order to develop into a large solid tumor mass however, a tumor foci must first establish a network of blood vessels in order to obtain the nutrients and oxygen required for further growth. This tumor-induced vasculature has received enormous interest as a target for antineoplastic therapy because a relatively small number of blood vessels are critical for the survival and continued growth of a much larger group of cancer cells. The disruption in the function of a single tumor blood vessel can result in an avalanche of ischaemic cell death and necrosis of thousands of tumor cells which depend on it for blood supply. In addition, the accessibility of the tumor vasculature by blood-borne antivascular therapeutics and the relatively stable genome of normal host vascular tissue can alleviate some of the problems of bioavailability and acquired drug resistance that plague conventional, anti-tumor based therapies.
Much of the research in anti-vascular cancer therapy has focused on understanding the process of new blood vessel formation or “angiogenesis” and identifying anti-angiogenic agents which inhibit the formation of new blood vessels. Angiogenesis is characterized by the proliferation of tumor endothelial cells and generation of new vasculature to support the growth of a tumor. This growth is stimulated by several growth factors produced by the tumor itself. One of these growth factors, Vascular Endothelial Growth Factor (“VEGF”), is relatively specific towards endothelial cells, by virtue of the restricted and up-regulated expression of its cognate receptor. Various anti-angiogenic strategies have been developed to inhibit this signaling process at one or more steps in the biochemical pathway in order to prevent the growth and establishment of the tumor vasculature. However, anti-angiogenic therapies act slowly and must be chronically administered to produce a desired effect.
Vascular Targeting Agents (“VTAs”), also known as Vascular Damaging Agents, are a novel class of antineoplastic drugs which attack solid tumors by selectively destroying the existing vasculature formed by angiogenesis. The cytotoxic mechanism of VTA action is quite divorced from that of anti-angiogenic agents. A single dose of VTA can cause a rapid and irreversible tumor vascular shutdown of existing tumor vasculature, leading eventually to tumor necrosis by induction of hypoxia and nutrient depletion. Other agents have been known to disrupt tumor vasculature but differ in that they also manifest substantial normal tissue toxicity at their maximum tolerated dose. In contrast, genuine VTAs retain their vascular shutdown activity at a fraction of their maximum tolerated dose.
Combretastatin A-4 Disodium Phosphate Prodrug (“CA-4DP”) is the lead drug of a group of VTAs currently in clinical trials as a VTA. This compound was initially isolated as Combretastatin A-4 (“CA-4”) from the stem wood of the African tree Combretum caffrum (Combretaceae). As described in U.S. Pat. No. 4,996,237, the entire disclosure of which is incorporated herein in entirety, CA-4 was synthesized and found to have tubulin binding activity. Moreover, CA-4 was found to be a potent inhibitor of microtubule assembly in tumor endothelium. However, due to the insolubility of CA-4 in human plasma, CA-4DP was developed and found to have superior activity as a VTA (U.S. Pat. No. 5,561,122, the entire disclosure of which is incorporated by reference). When administered to the bloodstream of a patient, the CA-4DP is cleaved to the active, tubulin-binding CA-4 by endogenous nonspecific phosphatases. It is thought that CA-4 selectively destabilizes the microtubule cytoskeleton of tumor endothelial cells, causing a profound alteration in the shape of the cell which ultimately leads to occlusion of the tumor blood vessel and shutdown of blood flow to the tumor (Kanthou and Tozer, Blood, 2002, 99(6): 2060-2069).
In vivo studies have confirmed that vascular damaging affects of CA-4P on tumor tissue far exceed its effects on normal tissues. While a dosage of 100 mg/kg can cause a 100-fold reduction in the tumor blood flow of a rat, blood flow is maintained at normal levels in vital tissues such as the heart, kidney, or small intestine (Tozer et al. Cancer Research, 1999, 59: 1626-1634, incorporated herein by reference). However, these studies did observe a substantial but transient increase in Mean Arterial Blood Pressure (“MABP”) in peripheral tissues, almost immediately following administration of CA-4P. The risks of VTA-induced hypertension are significant and may have life-threatening consequences, especially for human cancer patients who are burdened with an additional cardiac disorder. The complications associated with untreated drug-induced hypertension can include chest pains (angina pectoris), nausea, and headaches and may ultimately lead to tachychardia, congestive heart failure, kidney damage, stroke, loss of vision, or a myocardial infarction (heart attack) due to ischemia or lack of oxygen in the heart tissue.
It has been reported that anti-angiogenic agents can also cause an increase in blood pressure. In contrast with the acute and transient nature of the VTA-induced hypertension, this hypertension leads to a sustained increase in blood pressure that lasts for several weeks. International patent publication WO 01/74360 teaches a method for treating the chronic hypertension that is associated with administration of the VEGF Receptor Tyrosine Kinase (“RTK”) inhibitor 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy) quinazoline. The method comprises continuous dosing of the VEGF RTK inhibitor for several days followed by chronic administration of the Angiotensin Converting Enzyme (“ACE”) inhibitor Captopril. We have found that an antihypertensive agent is also effective in controlling the transient increase in blood pressure that is associated with a single dose of a VTA, and that, surprisingly, co-administration of a VTA and an anti-hypertensive does not compromise the desired tumor blood flow shutdown effect of the VTA.
Another surprising observation of the present invention is that while a single dose of CA-4P can cause minor cardiotoxicity within 24 hrs of treatment these symptoms appear to be reversible. Chemotherapy-induced cardiotoxicity has been a major problem with several other cancer therapies but is associated with long-term additive effects of cumulative doses of conventional cytotoxic agents over the period of months or years following initial treatment. Of the conventional chemotherapeutic drugs, anthracyclines are the most widely recognized as causing cardiac complications. These complications include cardiomyopathy, myocarditis, congestive heart failure, pericarditis, arrhythmia which are chronic symptoms associated with long term effect of cumulative dosing of chemotherapeutic agents on the order of weeks, months or years. These cardiotoxic effects are irreversible and progressive and must be treated with long-term medication. In fact, for some drugs, there is an established lifetime maximum for which a drug can be taken.
The prior art has suggested the use of antihypertensive agents for the treatment of symptomatic heart failure prior to or following long-term, cumulative dosing with anthracycline-type antineoplastic agents (Simbre et al., Current Treatment Options in Cardiovascular Medicine, 2001, 3: 493-505; Sacco et al., Eur J of Pharmacology, 2001, 414: 71-8.) but does not suggest the unexpected result that antihypertensive agents can protect the acute and transient cardiotoxicity that is associated with the VTA-induced shutdown of blood supply to a tumor.